Cancer cells are notorious for their ability to evade cancer-specific immune responses. Epigenetic modifications like DNA methylation and histone modifications through methylation or acetylation are implicated in several mechanisms underlying immune evasion. Drugs targeting epigenetic mechanisms can act on cancer cells but can also modulate the immune system. Therefore, we hypothesize that combining epigenetic drugs with mRNA- or DC-cancer vaccination represents a novel strategy for cancer treatment with potential synergistic effects. We will study a novel epigenetic drug, CM272, that inhibits both the activity of the histone methyltransferase G9a and DNA methyltransferase DNMT1. Quisinostat, a pan-histone deacetylase inhibitor, A366, a histone methyltransferase inhibitor, and decitabine, a pan-DNA methyltransferase inhibitor, will also be studied. The epigenetic drugs will be used at varying doses as single agents and in combination to maximize immunomodulating effects. We will study the mechanisms underlying the immunomodulatory activities. Moreover, we will combine the best-suited combination of epigenetic drugs with cancer vaccination, with their anti-tumor activity as outcome. Therefore, we will use predictive murine tumor models for melanoma and multiple myeloma. The preclinical data obtained during this project will help elucidate immunomodulatory effects of epigenetic drugs and define novel combination strategies suitable for clinical application.